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Observing the Bacterial Membrane Through Molecular Modeling and Simulation

Bacterial infections represent the second leading cause of death worldwide. The effectiveness of the available weaponry against these pathogens is progressively lowered by the constant insurgence multidrug-resistant bacterial strains. Antibacterial resistance constitutes nowadays a major concern for human health due to its social implications and economical impact, i.e. loss of human lives and increased mortality, morbidity, hospitalization length and healthcare costs.

One strategy to develop new and more efficient antibiotics that are less prone to generate resistance is to target and destabilize the bacterial membrane. In this context, investigating the physical and chemical principles governing the nature of bacterial membranes is of fundamental importance for understanding the functional role of lipid bilayers in shaping cells, promoting cellular signaling, and ensuring an active defense to external attacks, like those promoted by antimicrobial peptides (AMPs) produced by the immune system.

Molecular modeling and simulation stand as powerful resources to probe the properties of membranes at atomistic level. Therefore, in this project a team of scientists from the École Polytechnique Fédérale de Lausanne (EPFL) use the power of High Performance Computing (HPC) to characterize the structural and dynamic properties of the bacterial membrane using molecular dynamics (MD) simulation. In order to achieve this goal, the scientists (i) first created more accurate models of bacterial membrane constituents, (ii) then developed efficient tools for assembling realistic bacterial membrane systems, and (iii) and finally investigated the effect of a variety of AMPs on model systems of the inner membrane of E. coli.

The power of current HPC resources is key to observe and describe in simulation the atomistic details of membrane portions that are extended enough to be compared with the experimental setting. Moreover, the ability of current HPC highly parallel architectures is fully exploited to simulate the bacterial membrane for temporal intervals (i.e., for microseconds) that are relevant for biological interpretation. Therefore, it was key to benefit from the large allocation of a total of 45 mill core hours assigned through the Partnership for Advanced Computing in Europe, PRACE on the supercomputer JUQUEEN of GCS member centre JSC (Jülich Supercomputing Centre).

In conclusion, this project will contribute to develop deep and detailed insights into the organization and dynamics of the bacterial membrane. More importantly, we will seek to understand the principles of action of antimicrobial peptides with the final goal to use this information to aid the design of new and more powerful peptides with antimicrobial activity.

E. coli inner membrane and its interaction with antimicrobial peptides. A representative snapshot extracted from a molecular dynamics simulation is reported showing the E. coli inner membrane leaflets complexes with a key component of the innate immunity system, α-helical human cathelicidin LL-37 (in red cartoon representation, PDB id 2K6O). The inner membrane tends to be negatively charged due to the presence of several anionic phospholipids, such as phosphatidyglycerol (PG) and cardiolipin (CL) species. In this model system, the E. coli bilayer is faithfully reproduced by a mixture of phosphatidylethanolamine (in cyan), PG (in blue) and CL (in grey) species. Water molecules and ions solvating the system are not shown for clarity.